IE45186B1 - Phenoxypropanolamines - Google Patents

Abstract

Novel 1-(2-phenyl-2-hydroxyethylamino)-3-phenoxypropan-2-ols of formula I are prepared from compounds in which at least the amino group or one of the radicals R1, R2, R5 or R6 is protected, by hydrogenolytically removing the protective group. The symbols in formula I have the meaning given in the patent claim. The compounds of formula I have a cardiovascular action and furthermore have a vascular-dilating, antihypertensive and antiarrhythmic action.

Description

This invention relates to novel derivatives of 2phenyl-2-hydroxyethylamine having interesting pharmacological properties.

According to one feature of the present invention there 5 are provided compounds of the general formula [wherein R^ represents a hydrogen or halogen atom or a hydroxy,, amino, lower alkyl, lower alkoxy or lower acylamido groups R„ represents a hydrogen atom or a hydrojcy, lower alkyl, lower alkoxy or carboxamido groups Rg represents a hydrogen or halogen atom or a lower alkyl or lower alkoxy group; R^ represents a hydrogen atom or a methyl or ethyl group; and Rg and Rg, which may be the same or different, each repre15 sents a hydrogen or halogen atom or lower alkyl, lower alkoxy, benzyloxy, hydroxy, amino, cyano, carboxy, lower carί balkoxy, carboxamido, lower alkylenecarboxamido or lower acylamido groups; with the proviso that when R^ represents a hydrogen atom or a 20 4-hydroxy or 4-chloro group, Rg and Rg both represent hydrogen atoms, R^ represents a methyl group and R$ represents a hydrogen atom or 2-halo group, then Rg is other than a 4hydroxy or 4-benzyloxy group] and salts thereof.

The compounds of general formula I exist in the form cf racemates, mixtures of racemates and optical isomers and it will be appreciated that all such forms of the compounds of general formula I are within the scope 'of the present invention.

The expressions lower alkyl and lower alkoxy are used herein to refer to alkyl and alkoxy groups containing from 1 to 4 carbon atoms, which groups may be straightchained or branched as desired The expression lower acyiamido is used tc refer tc acyiamido groups the acyl moeifcy of which is derived from a lewer aliphatic carboxylic or lower 5ikanesulphonic acid having not more than 4 carbon atoms. Similarly the expression “lower alkylanecarboxanrido is used to refer to alkylenecarbox amido groups in wMii the alkylene radicals have not more than 4 carbon atoms.

The compounds of general formula I and physiologically acceptable salts thereof possess interesting pharmacological properties. In particular they show a cardiovascular action and blood-vessel dilating, antihypertensive and antiarrhythmic effects. Compounds according to the present invention which have been tested have exhibited a positively inotropic action with a very low frequency-increase and may 2o thus be useful as active ingredients for selectively active ' cardiotonics.

Preferred compounds according to the present invention by virtue of their favourable pharmacological properties are compounds in which: R^ represents a hydrogen, chlorine or bromine atom, or a hydroxy, C^_2 alkyl (especially methyl)', Cj_2 alkoxy (especially methoxy), acetylamido, propionylamido or methanesul fonamido group; &2 represents a hydrogen atom or a hydroxy, c^_2 alkyl (es10 pecially methyl) or C^_2 alkoxy (especially methoxy) group; represents a hydrogen, chlorine or bromine atom or a hydroxy, alkyl (especially methyl) or Cp.2 alkoxy (especially methoxy) group; R^ represents a hydrogen atom or a methyl group; and 15 Rg represents a hydrogen, fluorine, chlorine or bromine atom, or a C^_2 alkyl (especially methyl), Cj_2 alkoxy (especially methoxy) , hydroxy, cyano, carboxy, carboxamido, benzyloxy, or amino group, or a carbalkoxy, alkylenecarboxamido or acylamido group containing up to 3 carbon atoms; and salts thereof.

Particularly preferred compounds by virtue of their especially favourable pharmacological properties are the foilowing:- 4 - ι S 1 8 s 1- [2-(4-hydrcxyphenyl)-2-hydroxyethylamino]-3-(4cyanophanoxy)-propanol-(2); 1-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino]-3-(4tolyloxy)-propanol-(2); and salts thereof.

The compounds of general formula I according to the invention and salts thereof as well as ’possessing interesting pharmacclcz':ai properties hereinbefore described may also te useful as intermediates in the preparation of other pharmacologically active compounds. It will be appreciated that the salts of the compounds of general formula I (as hereinbefore defined) for use in medicine should be pharmacologically acceptable. Other salts, however, may be useful in the preparation of further compounds according to the invention or tha physiologically acceptable salts thereof or, as stated above, intermediates for the preparation of other pharmacologically active compounds.

The novel compounds of general formula I according to the invention may be prepared according to the following processes, which processes constitute further features of the present invention:1) By removing the protecting group or groups from a compound of formula (II) (wherein Rg and R^ are as hereinbefore defined; R? represents a hydrogen atom or an arylmethyl group; Rg is as defined for R^ or represents a hydroxy or amino group substituted by a hydrogenolytically or hydrolytically removable protecting group; Rg is as defined for R^ or represents a hydroxy group substituted by a hydrogenolytically or hydrolytically removable protecting group; and R^q and R.j_. are as defined for Sg and Κθ or represent hydroxy or amino groups substituted by hydrogenolytically or hydrolytically removable protecting groups; and at least one of tha groups Ry to R^^ represents or contains a protecting group).

Suitable protecting groups are for example aryl, methyl, alkanoyl, aroyl and tetrahydropyranyl groups, and for compounds with vicinal OH-groups, bifunctional groups such as for example a diarylmet’nylene group, can be used. Preferred protecting groups are benzyl and substituted benzyl groups, lower aliphatic acyl groups, benzoyl groups and diphenylmethylene groups. s 1 8 s Arylmethyl groups substituted at nitrogen atoms in the compound of formula II may be conveniently removed by catalytic hydrogenation in the presence of conventional hydrogenation catalysts, for example platinum, palladium or Raneynickel. Arylmethyl groups or diaryImethylene groups on oxygen atoms may be split off by catalytic hydrogenation or by hydrolysis with acids; and alkanoyl, aroyl or tetrahydropyranyl- groups ate desirably split off by hydrolysis.

If tha starting material of formula II has substituents which are required in the final product of formula ζ which substituents could however La modified under the conditions of the reaction, the reaction conditions can be made sufficiently mild that only thi protecting groups are removed, such conditions being familiar to those skilled in the art. It is also possible to start, for example, with a compound of formula Π wherein R^ and/or R^ represent carbalkoxy or carboxamido groups and to convert these groups simultaneously during the hydrolytic removal of the protecting groups into the corresponding compounds of formula I wherein R^ and/or Rg represent free carboxy groups. This may also be applicable to the other processes of the invention, The starting materials of formula II used in the above process may be obtained by conventional methods, for example by reacting an amine of formula - 7 10 δ1βδ 0-CH2-CHOH-CH2-NHR7 (III) (wherein R^ , R-^θ and R^j are as hereinbefore defined) with compounds of formula R„ ζ0χ CH— CHR, and/or (IVa) represents a halogen atom, for example a chlorine atom) in known manner.

The compounds of formula II may also be obtained by the later processes of the invention, and in these processes the erythro» or the threo-fom of the compound of formula II may be obtained, depending on the reducing agent used. 2) By reduction of the carbonyl group of a compound of (V) - 8 (wherein R^, R^, Rg, R^, Rg and Rg are as hereinbefore defined and one of the groups Y and Y' represents a -GO- group and the other a -CHOH- group).

The reduction of the carbonyl group is preferably effected a) with complex metal hydrides such as, for example, lithium aluminium hydride, sodium or potassium borohydride or sodium bis-(2-methoxyethoxy)aluminium hydride (SDMA); or b) with hydrogen in the presence of a hydrogenation catalyst such as for example, platinum, palladium or Raney-nickel.

When a compound of formula V wherein Y represents a carbonyl group and Rz an alkyl group is used, the final product may be produced in different diastereomeric forms, i.e. in the threo- or erythro- form. With reducing agents mentioned under a) above compounds of formula I in the threoforra are obtained, whilst with reducing agents mentioned under b), the erythro- form will be obtained, The starting materials of formula V may be obtained by conventional processes, for example by reacting a compound of formula (VI) '3 4»*® (wherein R^, R^R^, ^4’ Y anC^ X are as ^ere^n defined) with a compound of formula (VII) (wherein Rg, δθ and Y* are as herein defined). 3) By reacting a compound of formula Z°\ CH.

.CHR, (VIII) (wherein R^, Rg, Rg and R^_ are as herein defined) with compound of formula '5 o-ch2-choh-ch2-nh2 (IX) V (wherein Rg and Rg are as herein defined).

It should also be appreciated that the starting com pound of formula VIII may be replaced by a compound of formula - 10 fiSlSs (X) (wherein Rp R?Jan^ ^4 are as herein defined), which under the reaction conditions will produce a compound of formula VIII, 4) By reducing a Schiff's base of formula R.

CHOH-CHR, -h=CH-CToH-GH,-0 R JlLT ‘1 » 4 2 Rc (XIa) and/or of formu.a (wherein R,, R^, Ro, R^, R^ and Rg are as herein defined). The reduction may be conveniently effected with hydrogen and conventional hydrogenation catalysts or with complex metal hydrides.

) By reducing an acid amide of formula (Xlla) (wherein Rp R^, Rg, R^ and R^ areas herein defined) whereby a compound of formula I wherein R,. represents a hydrogen atom is produced; or by reacting an acid amide of formula (Xllb) (wherein Rp R^, Rg, R^, Rg· and R& are as herein defined), with a complex hydride such as, for example, lithium aluminium hydride, SDMA or diborane, 6) By hydrolysing a compound of formula (XHIa) - 12 4 S 1 8 β or a compound of formula R R R '3 (Xlllb) ‘6 (wherein R^, Rg, R-j, R^, Rg and Rg are'as herein defined and R represents a CO- or -CHR’. group, wherein R’ is a alkyl group or an aryl group).

The hydrolysis is conveniently effected in an acid or alkaline medium.

It is generally useful ta work at an elevated temperature in a mixture of water and a water-miscible solvent, for example, methanol, ethanol, or dioxan additionally in the presence of a base, preferably an alkali metal base.

This procs·-:? is preferably used for the preparation of final products of formula 1' which do not contain phenolic OH-groups, It may also be used for the production of starting materials for use in process 1), which contain hydrolysis-resistant protecting groups.

The oxazolidiuonea of formulae XHIa and XHIb may be obtained, for example, according to the following reaction schemes:“ 13 4Sl8® (Xllla’) or (XHIb·) (wherein Rp Rg, Rg, R^, Rg and Rg are as herein defined) 7) By reacting a compound of formula .:14$ 318 β Λ'-ΣΧ- CHOH-CHR R, -Ν-CH„ I I 2 CH —CHOH (XVIII) (wherein Rp Rp ^3 anc^ are as herein defined) with phenols of formula Rn HO ~ (XIX) (wherein Sg end Rg are as herein defined).

The reaction is conveniently effected at elevated temperatures. appropriately in a high boiling point, anhydrous solvent or mixture of solvents, for example in benzyl alcohol, and preferably in the presence of an alkali metal hydroxide and under a nitrogen atmosphere. The process serves, in general, for obtaining compounds of formula I according to the invention which do not contain phenolic hydroxy groups.

The following reaction scheme shows a method of producing the starting materials of formula XVIII:R, CHOH-CHR,-NH. 2 (XX) Cl-CH -CH- CH S. / Zx0 (XXI) - 15 (XVIII) Ί '3 choh-chr4-n· GH, CH, '2 CHOH (wherein Rp R2, &3 and R^ ate as herein defined) .

The processes according to the invention may be effected using the appropriate starting materials to produce directly individual optical isomers of the compounds of general formula I. Racemic mixtures produced by the processes according to the· invention may be resolved into the optically active compounds by conventional methods.

If separate optical isomers of the compound of formula I are required, they can be produced by using, for example, process . 2), wherein the starting materials of formula V are in the R- or S-form, that is with a chiral configuration of the CHOH-group. Than, according to the starting material, tha RS- or the RR-form or, the SS- or the SR-form, will be formed on reduction of the carbonyl group.

The basic compounds of general formula I produced by any of fche above processes may, if desired, be converted into salts thereof by conventional methods, and when produced as salts they may be converted into salts of other acids or into free bases.

Suitable acids for the preparation of acid addition - 16 *5188 salts of the compounds of general formula I (as hereinbefore defined) include, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, lactic acid, citric acid and maleic acid.

The starting materials used in any of the processes . according to the invention may be obtained by methods known per se.

As stated ah ve the compounds according to the present invention which have been tes ted exhibit a positively inotropic action whilst- the frequency-increase remains very low. Thus, we have found, for example, in the examination in the atrium of the isolated guinea-pig’s heart that the values obtained with the following compounds for the modification of amplitude (A) and frequency (F) in a conventional test with i eg active sijbstance/ml are 1-[2-(4-hydroxyphc-2-hydroxyethylamino]-3-(4-cyanophenoxy)-propanol-(2) A: + 37%, F: + 7 % and for 1-[2-(3,5-dihydroxyphenyl)-2-hydroxyethylamino J-3-(4-tolyloxy)-propanol-(2) A; + 36%, F: - 3%.

According to a further feature of the present invention there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I or a physiologically acceptable salt thereof in association - 17 with a pharmaceutical carrier or excipient.

The pharmaceutical compositions according to the invention can, for example, be in a form suitable for oral, rectal or parenteral administration. Suitable forms of ad5 ministration are, for example, tablets, coated tablets, capsules, tinctures, injection solutions or suppositories.

If desired, the compositions according to the invention can be in dosage unit form. Such dosage units conveniently contain 1 to 100 mg, and preferably 5 to 50 mg, of active ingredient. In general, the precise amount of active ingredient depends·οη the form of administration and body weight of the person to be treated.

Tablets may, for example, be obtained by mixing the active ingredient with known excipients, for example with inert diluents such as calcium carbonate, magnesium stearate or talcum and/or agents for obtaining sustained release, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetatephthalate or polyvinyl acetate. The tablets may, if desired, consist of several layers, for example to obtain sustained release or to avoid incompatibilities.

Coated tablets may be obtained by coating tablet cores prepared analogously to the tablets described above, with agents commonly applied for tablet coating, for example, -18 4&ise polyvinylpyrrolidone, shellac, gum arabic, talcum, titanium dioxide or sugar. To obtain sustained release or for avoid ing incompatibilities the core may also consist of several layers. The tablet coating may also consist of several layers whereby the excipients mentioned above for tablets may be used.

Capsules comprising the active ingredient according to the invention ir.uy be produced, for example, by mixing the active ingredient with inert carriers such as lactose or sorbitol and filling gelatin capsules with the mixture. 4S186 The following Examples illustrate the preparation of compounds according to the invention and pharmaceutical compositions containing them;Example 1 1-[2-(4-Hydroxyphenyl)-2-hydroxyethylamino]-3-(4-tolyloxy)propanol-(2) hydrochloride g of a-aminomethyl-4-benzyloxy-benzyl alcohol and 9 g of 2-(4-tolyloxymethyl)-oxirane are dissolved in 60 ml of ethanol and refluxed for 8 hours. The solution is allowed to cool overnight, and the product removed by suction filtration and dried. The compound obtained, l-[2-(4-benzyloxyphenyl)-2hydroxyethylamino]-3-(4-tolyloxyl)-propanol-(2), is dissolved in 50 ml of methanol and catalytically debenzylated after addition of palladium/charcoal 10% at room temperature and .15 normal pressure. After uptake of the calculated quantity of hydrogen, the catalyst is removed by suction filtration and the solvent is distilled off in a rotavapor. The residue is dissolved in acetonitrile and mixed with the calculated quantity of ethereal hydrochloric acid. The crystalline hydrochloride of l-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-(4-tolyloxy)-propanol -(2) is removedby suction filtration and dried. The product has a melting point of 146°C. *si8e Example 2 l-[2-(4-Hydroxyphenyl)-2-hydroxyethylamino]-3-(3-tolyloxy)propanol-(2) hydrochloride a) 15 g of 4'-benzyloxy-2-bromo-acetophenone are dissolved in 150 ml of acetonitrile. While stirring this solution, 13.5 g of l-benzylamino-3-(3-tolyloxy)-propanol-(2) (m.p. 76 - 77 C) and 6.9 g of anhydrous potassium carbonate are ,.dded. Tha reaction mixture is refluxed for 3 hours, cooled and suction filtered. The organic phase of the filtrate is mixed with the calculated quantity of ethereal hydrochloric acid. The hydrochloride of 4’benzyloxy - S-benzyl-M-Γ2-hydroxy-3-(3-tolyloxy)-propyl]2-amino-acetophenone (m,p, 147°C) is allowed to crystallize out overnight, and is then removed by suction fillo tration and dried, b) 21 g of the above hydrochloride salt are dissolved in water until the solution is weakly alkaline, mixed with ammonia and extracted with ether. After evaporation of the ether in vacuo, the residue is dissolved in 200 ml of alcohol and on addition of 1.5 g of sodium borohydride is reduced to 1-[2-(4-benzyloxyphenyl) -?.-hydroxy-N-benzy Ϊ -ethyl ami no [-3-(3- tolyloxy) -propanol-(2). The reaction mixture is then worked up by weakly acidifying with dilute acetic acid, the alcohol - 21 ,4S1S6 is distilled off in vacuo, and tha residue dissolved in water. After addition of ammonia it is extracted with ether. The solvent is distilled off in vacuo. the residue is taken up in acetonitrile and acidified with ethereal hydrochloric acid. The precipitated hydrochloride is removed by suction filtration and dried; m.p. 128°C. c) For the removal of both benzyl groups, the hydrochloride obtained from b) is dissolved in 10 times its.quantity of methanol. After addition of palladium/charcoal the solution is hydrogenated under standard conditions until the calculated quantity of hydrogen has been taken up.

It is suction filtered to remove the catalyst and the filtrate evaporated to dryness in vacuo; the residue is dissolved hot in acetonitrile. When cool, the crystalline 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3(3-tolyloxy)-propanol-(2)hydrochloride of melting point 149 - 150°C is obtained. 1-[2-(3-Hydroxyphenyl)-2-hydroxy-ethylamino]-3-(4- tolyl oxy)15.4 g of 3’-benzyloxy-α-bromomethyl-benzyl alcohol are refluxed tcgether with 13.5 g of N-benzyl-2-hydroxy-3-(4- 22 tolyloxy)-propylamine and 6.9 g of anhydrous potassium carbonate in 100 ml of acetonitrile for 5 hours. The product is removed by suction filtration and mixed with ethereal hydrochloric acid until weakly acid. The precipitated hydrochloride is immediately dissolved in methanol without further purification and after addition of palladium/charcoal is debenzylated catalytically. The catalyst is removed by suction filtration and che filtrate evaporated in vacuo to dryness, the residue dissolved in acetonitrile and allowed to cool slowly. The following day, the hydrochloride of 1[2- (3-hydroxyphenyl) - 2-hydroxy-ethylamino ]-2- ( 4-tolyloxy)propanol-(2) is removed by suction filtration and dried; m.P. 133 - 146°C.

Example 4 1-[2-(3-Hydroxyphenyl)-2“hydroxy-ethylamino]-3-(2-cyanophenoxy)-propanol- 2) fumarate__ a) 11.3 g of 2-(3-benzyloxyphenyl)-ethylene oxide (b.p,0 il52~155°C) and 16,8 g of l-benzylamino-3-(2cyanophenoxy)-propanol-(2) (m.p. 181-182°C) in 50 ml of ethanol are refluxed for 8 hours. Subsequently, the alcohol is distilled off in vacuo. the residue taken up in ethyl acetate and mixed with ethereal hydrochloric acid until weakly acid. The solution is allowed to stand overnight, suction filtered and dried. The hydrochloride of l-[2-(3-benzyloxyphenyI)-2-hydroxy-Nbenzy!“ethylamino]-3-(2-cyanophenoxy)-propanol-(2) is obtained having a melting point of 151 - 152°C. b) For debenzylation, the compound obtained under a) above 5 is dissolved in methanol and after addition of palladium/ charcoal shaken at room temperature until the calculated quantity of hydrogen has been taken up. Subsequently, the catalyst is removed by suction filtration, the product obtained from the filtrate is dissolved hot in 1θ alcohol and mixed with the calculated quantity of fumaric acid. It is allowed to cool slowly, suction filtered and dried. The fumarate of l-[2-(3-hydroxyphenyl)-2-hydroxy-ethylamino]-3~[2-cyanophenoxy]-propanol-(2) is obtained melting at 165-167°C, Example 5 1-[2-(3,5-dihydroxyphenyl)-2-hydroxy-ethylamino]-3-(4-tolyl5.4 g of £-cresol are dissolved in 50 ml of acetonitrile. 13,8 g of anhydrous potassium carbonate and 23.4 g of 3,520 dibenzyloxy-a-N-(3-chloro-2-hydroxy-propyl)-aminomethylbensylalcohol hydrochloride are then added. The reaction mixture is refluxed for 5 hours, suction filtered and the filtrate evaporated to dryness. The residue is dissolved in methanol and debenzylated catalytically under normal $81 a Q conditions. The reaction solution is filtered and the solvent distilled off, the residue is dissolved hot in acetonitrile, the calculated quantity of ethereal hydrochloric acid is added and the solution allowed to cool slowly. The crystals obtained of l-[2~(3,5-dihydroxyphenyl)-2-hydroxyethylamino]-3-[4-tolyloxy]-propanol-(2) hydrochloride are removed by suction filerstion and dried; m.p. 169 - 170°C.

Example 6 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylaminoJ-3-[2-mefchoxyphenoxy]-propanc-l-(2) sulfate 19,9 g of l-ainino-2-(2-methoxyphenoxy)-propanol-(2) together with 28.6 g of 4-benzyloxy-pheaylglyoxal-hemi-acetal (m.p. 77 - 80°C) in 300 ml of methanol are dissolved with heating to 4'J’G, The solution is allowed to stand overnight at room temperature, The following day, it is cooled to -10OC and 7.4 g of sodium borohydride are added in portions. During this procedure and the 5 hours reaction afterwards the temperature is not allowed to increase above 9°C. The reaction mixture is allowed to stand in a refrigerator overnight and the precipitated crystals of l-[2-(4-benzyloxyphenyl)-2-hydroxyethylamino]- 3- [2-methoxyphenoxy]-propanol(2) removed by suction filtration. They are dissolved in a 20-fold quantity of methanol, paliadium/charcoal is added - 25 4β1β* and the benzyl protecting group is removed by catalytic hydrogenation. After removing the catalyst by suction filtration, the solvent is distilled off in vacuo, the residue dissolved warm in a little alcohol and the calculated g quantity of concentrated sulfuric acid added. The sulfate of the l[2~(4-hydro3cyphenyl)-2-hydroxy-ethyiamino]~3-[2“ methoxyphenoxy]-gropsnol-(2) crystallizes out slowly, is removed by suction filtration and dried; m.p. 187 » 188°G„ Example 7 1- [ 2- ( 4-hydroxyphenyl) 2-hydroxy-ethylamino ]- 3- [ 4-carboxamido-phenoxy~i-propanol-(2) hydrochloride a) 14.9 g of l-benzylamino-3-(4“carboxamido-phenyl)propanone-(2) and 11,3 g of (4-benzyloxyphenyl)ethyleneoxide in 100 ml of alcohol are refluxed for 8 hours. The reaction mixture is allowed to react overnight at room temperature, and then 2 g of sodium borohydride are added. It Is now stirred for 2 hours at room temperature and then 2 hours at 70°C. The alcohol is distilled off in vacuo, the residue mixed with water and acidified with acetic acid. The solution is then made alkaline with ammonia and shaken several times with ethyl acetate. The organic phases are combined and the solvent distilled off in vacuo, the residue is dissolved . in boiling isopropanol and then cooled slowly. The pre25 cipitating crystals of 1-[2-(4-benzyloxylphenyl)-226 · hSISS hydroxy-N-benzyl.-ethylamino]- 3- [ 4-carboxamidophenoxy ]propanol-(2) are removed by suction filtration after some time and dried; m.p. 111-112CG. b) The dibenzyl compound obtained from a) is dissolved in 5 a 10»fold quantity of methanol and after addition of palladium/charcoal, debenzylated catalytically. After uptake of the calculated quantity of hydrogen, it is suction filtered to remove the catalyst, and the solvent is distilled off in vacuo, the residue dissolved in alcohol and then mixed with the calculated quantity of ethereal hydrochloric acid. The hydrochloride of the 1-[2 -{4-hydroxyphenyl}-2-hydroxy-ethylamino J-3-(4carbamidophenoxy)-propanoi-(2) crystallizes out. It is removed by suction filtration and dried in a drying cabinet with forced air circulation; m,p. 179 - 180°C, Example 8 1-[2»(4-Hydroxyphenyl)-2-hydroxy-ethylamino]-3-phenoxypropanol-(2) fumarate .2 g of 4-ber.zyloxy-N-[2-hydroxy-3-phenoxy)-propyl]-N20 benzyl-mandelic amide are dissolved in 200 ml of absolute tetrahydrofuran. While, stirring and simultaneously introducing nitrogen, 10 g of lithium aluminium hydride are added. The reaction mixture is refluxed for 5 hours, cooled and the excess lithium aluminium hydride decomposed by the slow - 27 ό5ΐθ6 ' addition of water. The solution is decanted off and evaporated to dryness. The residue is taken up in methanol and after addition of palladium/charcoal, dehenzylated catalytically. After uptake of the calculated quantity of hydrogen, the catalyst is removed by suction filtration, the filtrate evaporated in vacuo. The residue is dissolved in a little alcohol and a hot alcoholic solution of the calculated quantity of fumaric acid is added. On cooling, the fumarate of 1-[2-(4-hydroxyphenyl)-2-hydroxy-ethylamino]-3-phenoxy10 propanol-(2)a (m.p. 186 °C) is obtained.

Example 9 1- [ 2- ( 3,4- d ichlorophenyl)-2-hydroxy-e thylamino]-3-phenoxy15 A solution of 6 g of 3-L2-(3,4-dichlorophenyl)-2-hydroxyethylamino]-5-phenoxymethyloxazolidinone in 50 ml of ethanol is prepared to which 10 g of potassium hydroxide and 20 ml of water are added, and is then refluxed for 90 minutes. After cooling, the alcohol is distilled off in vacuo. The aqueous phase is extracted twice with ether, the ethereal phase washed with water and dried over magnesium sulfate. After distilling off the ether, the residue is dissolved in a little ethanol, formic acid added and - slowly - also ether. The colourless formate then crystallizes out. - 28 1-(2-Phenyl-2-hydroxy-ethylamino)-3-(2-cyanophenoxy)propanol-(2) hydrochloride g of l-(2-phenyl-2-hydroxyethyl)-azetidinol-(3) are dis5 solved in 15 ml of benzyl alcohol and 1.25 g of 2-cyanophenol and G.l g of potassium hydroxide are added. While stirring, the reaction mixture is heated for 5 hours to about 140*0. After co-- .'.ing, ether is added and is shaken thrice with 15 ml portions of 2 N hydrochloric acid. The aqueous phase is washed with ether and made alkaline with sodium hydroxide. The alkaline portions are taken up in ether and washed with water. The organic phase is dried over magnesium sulf cite, and the ether is subsequently distilled off.

The basic residue remaining is dissolved in ethyl acetate and mixed with ethereal hydrochloric acid until weakly acid. The hydrochloride is obtained as colourless crystals.

I Q JJ tf fo ίο fo H X) έ* parts by weight 1605 ” ' Example I Suppositories Composition: Active substance acc. to invention 5 lactose , pulverized cocoa butter The components are. processed to produce suppositories of 1.7 g of weight in the conventional way.

Example TI Composition: 1-[2-(3,5-dihydroxyphenyl)-2-hydroxysthyl- amino] - 3- ( 4-tolyloxy)-propanol-(2) 10 parts by weight lactose 490 tl 19 1» 15 corn starch 400 91 19 tl 1000 mg portions of tha finely pulverized mixture are filled 20 into hard gelatine capsules. Example III Tablets: Composition: 1-[2-(4-hydroxyphenyl)-2-hydroxyethyiamino]3-(4-cyanophenoxy)-propanol-(2) or its salts 5 parts by weight stearic acid 6 31 99 91 25 glucose 589 91 19 99 The components are processed to tablets, each weighing 60(1 mig, in conventianal manner. If desired, the content of active substance may be increased or decreased and the quantity of glucose correspondingly decreased or increased.

Claims (47)

1. Compounds of the general formula R, R CH-CH-NH-CH„-CH-CH„-0 ‘6 (I) [wherein / represents a hydrogen or halogen atom or a hydroxy, amino, lower alkyl, lower alkoxy or lower acyiamido group; Rg represents a hydrogen atom or a hydroxy, lower alkyl, lower alkoxy or carboxamido group; Rg represents s hydrogen or halogen atom or a lower alkyl or lower alkoxy group; R, represents a hydrogen atom cr a methyl or ethyl group; and Rg and Rg, which may be tiie same or different, each represents a hydrogen or h,.-.lo,r..: atom or lower alkyl, lower alkoxy, benzyloxy hydroxy, amino, cyano, carboxy, lower carbalkoxy, carboxamido, lower alkylenecarboxamido or lower acyiamido group; with the proviso that when R^ represents a hydrogen atom or a 4-hydroxy.or 4-chloro group, Rg and Rg both represent hydrogen atoms, R^ represents a methyl group and Rg represents a hydrogen atom or 2-halo group, then Rg is other than a 4-hydroxy or 4-benzyloxy group] and salts thereof.

2. Compounds as claimed in claim 1 wherein ν represents a hydrogen, chlorine or bromine atom, or a hydroxy, Cj_ 2 alkyl, C^_ 2 alkoxy, acetylamido, propionylamido or methanesulphonamido group; R 2 represents a hydrogen atom or a hydroxy, C^_ 2 alkyl 5 or C^_ 2 alkoxy group; Rg represents a hydrogen, chlorine or bromine atom or a hydroxy, Cq_ 2 alkyl or C^_ 2 alkoxy group; represents a hydrogen atom or a methyl group; and Rg represents a hydrogen, fluorine, chlorine or bromine 10 atom; a Cj_ 2 alkyl, C^_ 2 alkoxy, hydroxy, cyano, carboxy, carboxamido, benzyloxy or amino group; or a carbalkoxy, alkylenecarboxamido or acylamido group containing up to 3 carbon atoms.

3. Compounds as claimed in claim 2 wherein Rp R 2 , Rg and 15 Rg each represents a methyl or methoxy group.

4. 1- [ 2- (4-Hydroxyphenyi}-2-hydroxyethylamino]-3-(4-cyanophenoxy)-propanol-(2) and salts thereof.

5. 1=[2»(3,5-Dihydroxyphenyl)-2-hydroxyethylamino]-3-(4tolyloxy)-propanol-(2) and salts thereof. 20

6. Compounds as claimed in claim 1 as herein specifically disclosed with the exception of those compounds claimed in either of claims 4 and 5.

7. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises removing the 4Sis e protecting group or groups from a compound of formula /wherein R„ and R, are as defined in claim 1: R, represents s J '4 / a hydrogen atom or an arylmethyl group· Κθ is as defined in 5 claim 1 for R or represents a hydroxy or amino group substituted by a hydrogenolytically or hydrolytically removable protecting group; Rg is as defined in claim 1 for or re “ presents a hydroxy group substituted by a hydrogenolytically or hydrolytically removaoie protecting group; and R^ and 10 R, are as defined in claim 1 for R^ and Rg or represent hydroxy or amino group:? substituted by hydrogenolytically or hydrolytically r./·.. vable protecting groups; and at least one of the groups Ry to R-^ represents or contains a protecting group). ]g

8. , A process as claimed in claim 7 wherein the protectinggroup or groups is/are aryl, methyl, alkanoyl, aroyl or tetrahydropyranyl group(s), or, where the compound of formula II contains vicinal hydroxy groups, a diaryImethylene group.

9. A process as claimed in claim 8 wherein the protecting 20 group or groups is/are benzyl or substituted benzyl groups, Λ^ 5 ·® 6 lower aliphatic acyl groups, benzoyl groups or diphenylmethylene groups.

10. A process as claimed in any of claims 7 to 9 wherein arylmethyl protecting groups substituted at nitrogen atoms in the compound of formula II are removed by catalytic hydrogenation in the presence of a platinum, palladium or Raney-nickel catalyst.

11. A process as claimed in either of claims 8 and 9 wherein arylmethyl or diarylmethylene protecting groups substituted at oxygen atoms in the compound of formula II are removed by catalytic hydrogenation or by acid hydrolysis.

12. A process as claimed in either of claims 8 and 9 wherein alkanoyl, aroyl or tetrahydropyranoyl protecting groups in the compound of formula II are removed by hydrolysis.

13. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reducing the carbonyl group of a compound of formula (wherein R,, kji ®y,,j R5 an< i kg are as defined in claim 1 and one of the groups Y and Y* represents a -CO- group and the other a -CHOH- group).

14. A process as claimed in claim 13 wherein the reduction is effected with a complex metal hydride.

15. A process as claimed in claim 14 wherein the complex metal hydride comprises lithium aluminium hydride, sodium or 5 potassium borohydride or sodium bis-(2-methoxyethoxy)-aluminium hydride.

16. A process ac claimed in claim 13 wherein the reduction is effected by hydrogenation in the presence of a platinum, palladium or Raney-nickel catalyst. 10

17. , A process fcr the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula CH—CHR (VIII) (wherein R,, R^ and are as defined in claim 1) with a 15 compound of formula Rt: (IX) R' (wherein R c and Rg are as defined in claim 1).

18. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula R, CHOH-CHR,—Cl 4 (X) 5 (wherein Rp r 2 ,r 3 snd£,are as defined in claim 1) with a compound of formula IX as defined in claim 17.

19. , A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reducing a compound of formula P 'l ?£>y~-CH0H-CHR,-N=CH-CHOH-CH 9 -0 (XIa) and/or of formula (Xlb) (wherein Rp Rg, R,, R^, Sg and Rg are as defined in claim 1). 15

20. , A process as claimed in claim 19 wherein the reduction 4 s ι ε s is effected by catalytic hydrogenation or by reduction with a complex metal hydride.

21. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reducing a compound of formula (wherein R, , R^, R„, R_ and R^ are as defined in claim 1) whereby a compound of formula I wherein represents a hydrogen atom is obtained: or of formula Ri X -ν' CHOfe- Gbit .-RH-GO-GHOH-GH--G 4 2 (XIlb) (wherein R,. R ?J Rj, R^, R^ and R ; - are as defined in claim 1); with a complex hydride.

22. A process as claimed in claim 21 wherein the complex hydride comprises lithium aluminium hydride, sodium bis-(2methoxyetkoxy)*aluminium hydride or diborane.

23. , · A process for the preparation of compounds of general δ formula I as defined in claim 1 which comprises hydrolysing a compound of formula or a compound of formula (XHIa) (Xlllb) (wherein R 1 , Rgs ^3» kg ail ^ Rg sre as defined in claim 1 and R represents a -CO- or -GHR’- group in which R’ is a G-£_q alkyl group or an aryl group).

24. A process as claimed in claim 23 wherein the hydrolysis 10 is effected in an acid or alkaline medium.

25. A process as claimed in either of claims 23 and 24 wherein the hydrolysis is effected at an elevated temperature in the presence of a mixture of water and a water-miscible solvent. 15

26. A process as claimed in claim 25 wherein the watermiscible solvent is methanol, ethanol or dioxan,

27. A process as claimed in either of claims 25 and 26 wherein the reaction is effected in the presence of an s S18 6 alkali metal base.

28. A precess for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula R, CHOH-CHR.-N— 4 i i ! CBL • CH, i £ -CHOH (XVIII) (wherein Rp Rg, Rj and R^ are as defined in claim 1) with a compound of formula I? p A 6 (wherein R c and - . are as defined in claim 1). 10

29. A process as claimed in claim 28 wherein the reaction is effected at an elevated temperature.

30. A process as claimed in either of claims 28 and 29 wherein the reaction is effected in the presence of a high boiling point, anhydrous solvent or mixture of solvents. 15

31. A process as claimed in claim 30 wherein the solvent comprises benzyl alcohol.

32. A process as claimed in any of claims 28 to 31 wherein the reaction is effected in the presence of an alkali metal hydroxide.

33. A process as claimed in any of claims 28 to 32 wherein the reaction is effected in the presence of a nitrogen atmosphere.

34. A process for the preparation of optically active isomers of the compounds of general formula I as defined in claim 1 which comprises using an optically active starting material in a process as claimed in any of claims 7 to 33.

35. A process for the preparation of optically active isomers of the compounds of general formula I which comprises resolving a racemic mixture of a compound of formula I prepared by a process claimed in any of claims 7 to 33.

36. A process as claimed in any of claims 7 to 35 wherein the compound of formula 1 as defined in claim 1 produced is converted into a salt thereof.

37. A process for the preparation of compounds of general formula I as defined in claim 1 and salts thereof substantially as herein described.

38. A process for the preparation of compounds of general formula I as defined in claim 1 and salts thereof substantially as herein described in any of Examples 1 to 10.

39. Compounds as claimed in claim 1, whenever prepared by a process as claimed in any of claims 7 to 38. **18 g

40. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof in association with a pharmaceutical carrier or excipient. 5

41. Compositions as claimed in claim 40 in a form suitable foi· oral, rectal or parenteral administration.

42. Compositions as claimed in either of claims 40 and 41 in the form cf tablets, coated tablets, capsules, tinctures, injection solutions or suppositories. 10

43. , Compositions as claimed in any of claims 40 to 42 in dosage unit form,

44. Compositions as claimed in claim 43 wherein each dosage unit contains 1 to 100 mg of the said active ingredient,

45. Compositions as claimed in claim 44 wherein each dosage 15 unit contains 5 to 50 ng of the said active ingredient,

46. Pharmaceutical compositions as claimed in claim 40 substantially as herein described.

47. Pharmaceutical compositions as claimed in claim 40 substantially as herein described in any of Examples I to III.